Summary Background CTX0E03 is an immortalised human neural stem-cell line from which a drug product (CTX-DP) was developed for allogeneic therapy. Dose-dependent improvement in sensorimotor function ...in rats implanted with CTX-DP 4 weeks after middle cerebral artery occlusion stroke prompted investigation of the safety and tolerability of this treatment in stroke patients. Methods We did an open-label, single-site, dose-escalation study. Men aged 60 years or older with stable disability (National Institutes of Health Stroke Scale NIHSS score ≥6 and modified Rankin Scale score 2–4) 6–60 months after ischaemic stroke were implanted with single doses of 2 million, 5 million, 10 million, or 20 million cells by stereotactic ipsilateral putamen injection. Clinical and brain imaging data were collected over 2 years. The primary endpoint was safety (adverse events and neurological change). This trial is registered with ClinicalTrials.gov , number NCT01151124. Findings 13 men were recruited between September, 2010, and January, 2013, of whom 11 (mean age 69 years, range 60–82) received CTX-DP. Median NIHSS score before implantation was 7 (IQR 6–8) and the mean time from stroke was 29 (SD 14) months. Three men had subcortical infarcts only and seven had right-hemisphere infarcts. No immunological or cell-related adverse events were seen. Other adverse events were related to the procedure or comorbidities. Hyperintensity around the injection tracts on T2-weighted fluid-attenuation inversion recovery MRI was seen in five patients. At 2 years, improvement in NIHSS score ranged from 0 to 5 (median 2) points. Interpretation Single intracerebral doses of CTX-DP up to 20 million cells induced no adverse events and were associated with improved neurological function. Our observations support further investigation of CTX-DP in stroke patients. Funding ReNeuron Limited.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract
The Mouse Phenome Database (MPD; https://phenome.jax.org) is a widely used resource that provides access to primary experimental trait data, genotypic variation, protocols and analysis tools ...for mouse genetic studies. Data are contributed by investigators worldwide and represent a broad scope of phenotyping endpoints and disease-related traits in naïve mice and those exposed to drugs, environmental agents or other treatments. MPD houses individual animal data with detailed, searchable protocols, and makes these data available to other resources via API. MPD provides rigorous curation of experimental data and supporting documentation using relevant ontologies and controlled vocabularies. Most data in MPD are from inbreds and other reproducible strains such that the data are cumulative over time and across laboratories. The resource has been expanded to include the QTL Archive and other primary phenotype data from mapping crosses as well as advanced high-diversity mouse populations including the Collaborative Cross and Diversity Outbred mice. Furthermore, MPD provides a means of assessing replicability and reproducibility across experimental conditions and protocols, benchmarking assays in users' own laboratories, identifying sensitized backgrounds for making new mouse models with genome editing technologies, analyzing trait co-inheritance, finding the common genetic basis for multiple traits and assessing sex differences and sex-by-genotype interactions.
Extracellular ATP plays a role in nociceptive signalling and sensory regulation of visceral function through ionotropic receptors
variably composed of P2X 2 and P2X 3 subunits. P2X 2 and P2X 3 ...subunits can form homomultimeric P2X 2 , homomultimeric P2X 3 , or heteromultimeric P2X 2/3 receptors. However, the relative contribution of these receptor subtypes to afferent functions of ATP in vivo is poorly understood. Here we describe null mutant mice lacking the P2X 2 receptor subunit (P2X 2 â/â ) and double mutant mice lacking both P2X 2 and P2X 3 subunits (P2X 2 /P2X 3 Dblâ/â ), and compare these with previously characterized P2X 3 â/â mice. In patch-clamp studies, nodose, coeliac and superior cervical ganglia (SCG) neurones from wild-type mice responded
to ATP with sustained inward currents, while dorsal root ganglia (DRG) neurones gave predominantly transient currents. Sensory
neurones from P2X 2 â/â mice responded to ATP with only transient inward currents, while sympathetic neurones had barely detectable responses. Neurones
from P2X 2 /P2X 3 Dblâ/â mice had minimal to no response to ATP. These data indicate that P2X receptors on sensory and sympathetic ganglion neurones
involve almost exclusively P2X 2 and P2X 3 subunits. P2X 2 â/â and P2X 2 /P2X 3 Dblâ/â mice had reduced pain-related behaviours in response to intraplantar injection of formalin. Significantly, P2X 3 â/â , P2X 2 â/â , and P2X 2 /P2X 3 Dblâ/â mice had reduced urinary bladder reflexes and decreased pelvic afferent nerve activity in response to bladder distension.
No deficits in a wide variety of CNS behavioural tests were observed in P2X 2 â/â mice. Taken together, these data extend our findings for P2X 3 â/â mice, and reveal an important contribution of heteromeric P2X 2/3 receptors to nociceptive responses and mechanosensory transduction within the urinary bladder.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Ionic liquids are a diverse range of charged chemicals with low volatility and often liquids at ambient temperatures. This characteristic has in part lead to them being considered ...environmentally-friendly replacements for existing volatile solvents. However, methylimidazolium ionic liquids are slow to break down in the environment and a recent study at Newcastle detected 1 octyl 3 methylimidazolium (M8OI) – an 8 carbon variant methylimidazolium ionic liquid - in soils in close proximity to a landfill site. The current M8OI toxicity database in cultured mammalian cells, in experimental animal studies and in model indicators of environmental impact are reviewed. Selected analytical data from the Newcastle study suggest the soils in close proximity to the landfill site, an urban soil lacking overt contamination, had variable levels of M8OI. The potential for M8OI - or a structurally related ionic liquid – to trigger primary biliary cholangitis (PBC), an autoimmune liver disease thought to be triggered by an unknown agent(s) in the environment, is reviewed.
•“Ionic liquids” defines a diverse range of chemicals proposed as green chemicals.•There are limited data in mammalian systems regarding their potential toxicity.•The ionic liquid M8OI has been found at high levels in the environment.•M8OI inhibits mitochondrial function and induces mammalian cell apoptosis.•M8OI is metabolised to a lipoic acid mimetic and may be a hazard trigger for PBC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•Soil samples around landfill waste sites were screened for their ability to activate xenobiotic receptors and toxicity.•Xenoestrogens were present at higher levels in soils around a ...landfill site.•An ionic liquid was found to be present at high levels in two soil sampling sites near landfill.•The ionic liquid inhibited cellular oxidative phosphorylation, was toxic to a liver progenitor cell line and induced apoptosis.•The ionic liquid was metabolised by human hepatocytes to a carboxylic acid that bore structural similarity to lipoic acid.
Primary biliary cholangitis (PBC) is an autoimmune-associated chronic liver disease triggered by environmental factors, such as exposure to xenobiotics, which leads to a loss of tolerance to the lipoic acid-conjugated regions of the mitochondrial pyruvate dehydrogenase complex, typically to the E2 component. We aimed to identify xenobiotics that might be involved in the environmental triggering of PBC.
Urban landfill and control soil samples from a region with high PBC incidence were screened for xenobiotic activities using analytical, cell-based xenobiotic receptor activation assays and toxicity screens.
A variety of potential xenobiotic classes were ubiquitously present, as identified by their interaction with xenobiotic receptors – aryl hydrocarbon receptor, androgen receptor and peroxisome proliferator activated receptor alpha – in cell-based screens. In contrast, xenoestrogens were present at higher levels in soil extracts from around an urban landfill. Furthermore, two landfill sampling sites contained a chemical(s) that inhibited mitochondrial oxidative phosphorylation and induced the apoptosis of a hepatic progenitor cell. The mitochondrial effect was also demonstrated in human liver cholangiocytes from three separate donors. The chemical was identified as the ionic liquid 3-methyl-1-octyl-1H-imidazol-3-ium+ (M8OI) and the toxic effects were recapitulated using authentic pure chemical. A carboxylate-containing human hepatocyte metabolite of M8OI, bearing structural similarity to lipoic acid, was also enzymatically incorporated into the E2 component of the pyruvate dehydrogenase complex via the exogenous lipoylation pathway in vitro.
These results identify, for the first time, a xenobiotic in the environment that may be related to and/or be a component of an environmental trigger for PBC. Therefore, further study in experimental animal models is warranted, to determine the risk of exposure to these ionic liquids.
Primary biliary cholangitis is a liver disease in which most patients have antibodies to mitochondrial proteins containing lipoic acid binding site(s). This paper identified a man-made chemical present in soils around a waste site. It was then shown that this chemical was metabolized into a product with structural similarity to lipoic acid, which was capable of replacing lipoic acid in mitochondrial proteins.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Despite calls in the literature, little is known about how dimensions of a social and task nature relate to each other in school and out-of-school learning environments. This study explored whether ...interpersonal and task dimensions of the youth sport environment, as perceived by young people, are related, and, if so, how they are related. We used data from 310 adolescent sport participants from eastern Canada (Mage = 14.69 ± 1.60 years; 54.8% girls). Participants completed comprehensive assessments of interpersonal dimensions of the sport environment and the characteristics of learning activities they do in practices. We used canonical correlation analysis to examine the multivariate shared relationship between the variable sets. The relationship was largely captured by the first three functions in the canonical model. The first two functions revealed areas of intersection between perceptions of interpersonal and practice-based activity factors in the form of supports and challenges for the learning and development process in sport. Accounting for the participants’ age, the third function displayed characteristics consistent with recent descriptions of complex environments in youth sport. The findings suggest that adolescents’ perceptions of interpersonal- and task-related features of sport are interdependent, and highlight the relevance of including variables assessing both factors in studies that attempt to characterize and understand learning environments in sport and other achievement domains. Findings also afford new insights into whether dimensions of a social and task nature are complementary, and inadequacies in one dimension can be attenuated by strengths in another or not.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
P2X receptors in peripheral neurons Dunn, P M; Zhong, Y; Burnstock, G
Progress in neurobiology,
10/2001, Volume:
65, Issue:
2
Journal Article
Peer reviewed
P2X receptors are a family of ligand-gated ion channels, activated by extracellular ATP. The seven subunits cloned (P2X1-7) can assemble to form homomeric and heteromeric receptors. Peripheral ...neurons of neural crest origin (e.g. those in dorsal root, trigeminal, sympathetic and enteric ganglia) and placodal origin (e.g. those in nodose and petrosal ganglia) express mRNAs for multiple P2X subunits. In this review, we summarize the molecular biological, electrophysiological and immunohistochemical evidence for P2X receptor subunits in sensory, sympathetic, parasympathetic, pelvic and myenteric neurons and adrenomedullary chromaffin cells. We consider the pharmacological properties of these native P2X receptors and their physiological roles. The responses of peripheral neurons to ATP show considerable heterogeneity between cells in the same ganglia, between ganglia and between species. Nevertheless, these responses can all be accounted for by the presence of P2X2 and P2X3 subunits, giving rise to varying proportions of homomeric and heteromeric receptors. While dorsal root ganglion neurons express predominantly P2X3 and rat sympathetic neurons express mainly P2X2 receptors, nodose and guinea-pig sympathetic neurons express mixed populations of P2X2 and heteromeric P2X2/3 receptors. P2X receptors are important for synaptic transmission in enteric ganglia, although their roles in sympathetic and parasympathetic ganglia are less clear. Their presence on sensory neurons is essential for some processes including detection of filling of the urinary bladder. The regulation of P2X receptor expression in development and in pathological conditions, along with the interactions between purinergic and other signalling systems, may reveal further physiological roles for P2X receptors in autonomic and sensory ganglia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract This study aimed to identify different groups of adolescents who have distinct profiles based upon their perceptions of interpersonal and activity-based dimensions of the sport environment. ...A sample of 310 adolescents from Eastern Canada (Mage = 14.69 ± 1.60 years; 54.8% girls) completed questionnaires assessing selected interpersonal, activity-based, demographic and sport-specific variables. Using TwoStep Cluster Analysis, we identified three groupings of adolescent sport participants. Consistent with the literature, we labeled these groups ‘negative context,’ ‘positive context,’ and ‘complex context,’ respectively. As expected, participants in the last two groups reported greater enjoyment, perceived competence, and commitment to sport. Further, participants in the ‘complex context’ group showed the highest levels of sport commitment. We draw on insights from Csikszentmihalyi's theory of complexity and relational conceptions of compensation and resilience to interpret the findings, and offer an alternative account of contextual conditions suitable for adolescents involved in competitive sport.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UL, UM, UPCLJ, UPUK, ZRSKP
Black carbon (BC), the product of incomplete combustion of fossil fuels and biomass (called elemental carbon (EC) in atmospheric sciences), was quantified in 12 different materials by 17 laboratories ...from different disciplines, using seven different methods. The materials were divided into three classes: (1) potentially interfering materials, (2) laboratory‐produced BC‐rich materials, and (3) BC‐containing environmental matrices (from soil, water, sediment, and atmosphere). This is the first comprehensive intercomparison of this type (multimethod, multilab, and multisample), focusing mainly on methods used for soil and sediment BC studies. Results for the potentially interfering materials (which by definition contained no fire‐derived organic carbon) highlighted situations where individual methods may overestimate BC concentrations. Results for the BC‐rich materials (one soot and two chars) showed that some of the methods identified most of the carbon in all three materials as BC, whereas other methods identified only soot carbon as BC. The different methods also gave widely different BC contents for the environmental matrices. However, these variations could be understood in the light of the findings for the other two groups of materials, i.e., that some methods incorrectly identify non‐BC carbon as BC, and that the detection efficiency of each technique varies across the BC continuum. We found that atmospheric BC quantification methods are not ideal for soil and sediment studies as in their methodology these incorporate the definition of BC as light‐absorbing material irrespective of its origin, leading to biases when applied to terrestrial and sedimentary materials. This study shows that any attempt to merge data generated via different methods must consider the different, operationally defined analytical windows of the BC continuum detected by each technique, as well as the limitations and potential biases of each technique. A major goal of this ring trial was to provide a basis on which to choose between the different BC quantification methods in soil and sediment studies. In this paper we summarize the advantages and disadvantages of each method. In future studies, we strongly recommend the evaluation of all methods analyzing for BC in soils and sediments against the set of BC reference materials analyzed here.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
The Mouse Phenome Database (MPD; https://phenome.jax.org) is a widely accessed and highly functional data repository housing primary phenotype data for the laboratory mouse accessible via ...APIs and providing tools to analyze and visualize those data. Data come from investigators around the world and represent a broad scope of phenotyping endpoints and disease-related traits in naïve mice and those exposed to drugs, environmental agents or other treatments. MPD houses rigorously curated per-animal data with detailed protocols. Public ontologies and controlled vocabularies are used for annotation. In addition to phenotype tools, genetic analysis tools enable users to integrate and interpret genome–phenome relations across the database. Strain types and populations include inbred, recombinant inbred, F1 hybrid, transgenic, targeted mutants, chromosome substitution, Collaborative Cross, Diversity Outbred and other mapping populations. Our new analysis tools allow users to apply selected data in an integrated fashion to address problems in trait associations, reproducibility, polygenic syndrome model selection and multi-trait modeling. As we refine these tools and approaches, we will continue to provide users a means to identify consistent, quality studies that have high translational relevance.
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